RSV is the leading viral cause of lower respiratory illness and hospitalization in young children, yet there isn't an approved vaccine. The vast majority of children infected with RSV suffer from a mild upper respiratory tract infection; however, severe lower respiratory infection develops in 20-30% of RSV-infected children, resulting in >130,000 pediatric hospitalizations annually in the United States. Given the degree of RSV-associated hospitalizations, morbidity, and mortality, the development of an RSV vaccine is a high public health priority. The history of failed RSV vaccines, such as formalin-inactivated virus, attenuated viruses, and purified protein subunit vaccines clearly shows the need for a new vaccine design. Fortunately, there are new vaccine designs based on understanding the immunobiology of natural RSV infection, the failed vaccines, and the safe and effective passive immunotherapy Synagistm. The new vaccine designs focus on inducing neutralizing antibodies for protection and cytolytic cellular responses to clear infection. The strategy for this SBIR was formulated on the recent demonstration of protection in animal models of RSV by adenoviral vector vaccines and the recognition of pre-existing immunity as an impediment to effective and safe immunization. GenVec's strategy to use a replication-defective adenovirus vectored vaccine for RSV is based on the clinically proven capability of adenovirus vectored vaccines to induce antibody, CD8+ T-cell, and Th1 type responses. These considerations resulted in the underlying hypothesis that maternal immunity in the neonate to both the vaccine vector and RSV can be circumvented by vaccine design. We have identified a non-human adenovirus vector, SAV7, that has been demonstrated to have comparable efficacy to Ad5 vectors in animal models of RSV protection. The human population should be nave to the non-human adenovirus vector. We will be able to rapidly test the maternal immunity hypothesis in preclinical models, and with positive results, advance to human clinical testing. Our probability of success is increased by our experience with key RSV animal models, adenoviral vector vaccines, and our collaboration with a leader in the field of RSV research, Barney Graham, VRC, NIAID. The aims of the project are the verification of low human seroprevalence of the non-human adenovirus vectors and in vivo assessment (cotton rat model) of the effect of pre-existing immunity on vaccine vector-induced immune responses to RSV. Both human adenovirus immunity and passive RSV antibody immunity will be modeled. Successful completion of the aims and demonstration of no effect of pre-existing immunity on the immunogenicity of the SAV7 RSV vaccine vector will justify continuing the project to Phase II. Key aspects of Phase II would be pre-clinical testing of candidate vaccines in regimens appropriate for inducing protection against RSV in infants less than two months old and, subsequently, cGMP manufacture of clinical material. We estimate the additional time and funding necessary to bring this product to clinical testing after the completion of Phase I to be 3 years and 5 million dollars. PUBLIC HEALTH RELEVANCE: Respiratory syncytial virus (RSV) is the leading viral cause of lower respiratory illness and hospitalization in young children and has long been recognized as a priority disease for a vaccine. We propose a method of vaccination that, despite pre-existing immunity to human adenovirus and RSV, will induce an antibody and balanced helper and killer T-cell response against RSV without causing enhanced disease. In phase I we will test the hypothesis that RSV-specific immune responses induced by a novel replication-deficient adenovirus vector derived from non-human adenovirus will not be inhibited by human viral immunity.